美国凯斯西储大学医学院的研究人员已确定一个防止血管形成阻塞的重要遗传因子，这一发现或将导致心血管疾病的新疗法。该研究成果发表在11月19日《临床研究期刊》上。
研究小组发现，负责调节血管内皮细胞的遗传因子KLF4的短缺，将更易形成有害牙菌斑和脂肪沉积。此外，他们还发现，KLF4不足使血管更易形成斑块。斑块积累（即动脉粥样硬化）使血管变窄，为血栓形成导致心脏病和中风发作打下基础。相反，足够水平的KLF4将保护血管内衬免遭可触发形成斑块和凝块的毒素和其他有害物质的侵害。
研究人员表示，该研究回答了关于血管健康的一个基本问题，即发现了KLF4是内皮细胞最主要功能的主调控器。这些遗传因子的水平因人体疾病而改变，因此以此为靶标或是可行的治疗策略。
研究人员目前正在开发工具，以发现可增加KLF4水平的小分子。从长远来看，研究人员的目标是鉴别出一类新的分子，并藉此研制出一种药物，与现已用于心脏疾病治疗的药物共同发挥作用。另一种可能则是对现有药物进行改进以提高KLF4水平。(生物谷Bioon.com)
DOI:10.1172/JCI66056
PMC:
PMID:
Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice
Guangjin Zhou1, Anne Hamik1, Lalitha Nayak1, Hongmei Tian1, Hong Shi1, Yuan Lu1, Nikunj Sharma1, Xudong Liao1, Andrew Hale1, Lauren Boerboom2, Ryan E. Feaver3, Huiyun Gao1, Amar Desai4, Alvin Schmaier3, Stanton L. Gerson4, Yunmei Wang1, G. Brandon Atkins1, Brett R. Blackman2,3, Daniel I. Simon1 and Mukesh K. Jain1
The endothelium regulates vascular homeostasis, and endothelial dysfunction is a proximate event in the pathogenesis of atherothrombosis. Stimulation of the endothelium with proinflammatory cytokines or exposure to hemodynamic-induced disturbed flow leads to a proadhesive and prothrombotic phenotype that promotes atherothrombosis. In contrast, exposure to arterial laminar flow induces a gene program that confers a largely antiadhesive, antithrombotic effect. The molecular basis for this differential effect on endothelial function remains poorly understood. While recent insights implicate Kruppel-like factors (KLFs) as important regulators of vascular homeostasis, the in vivo role of these factors in endothelial biology remains unproven. Here, we show that endothelial KLF4 is an essential determinant of atherogenesis and thrombosis. Using in vivo EC-specific KLF4 overexpression and knockdown murine models, we found that KLF4 induced an antiadhesive, antithrombotic state. Mechanistically, we demonstrated that KLF4 differentially regulated pertinent endothelial targets via competition for the coactivator p300. These observations provide cogent evidence implicating endothelial KLFs as essential in vivo regulators of vascular function in the adult animal.
